Retinal degenerations are the most common cause of blindness in the Western world. Over 5% of the population will, at some point in their lives, suffer from retinal degeneration. Although we have made great strides in identifying genes responsible for much retinal degeneration, strategies for repairing the diseased retina have remained elusive. Recent studies suggest that the mammalian retina harbors progenitors that can restore lost neurons, albeit with very low efficiency. One goal of neurobiologists studying the retina is to identify strategies for inducing a regenerative response that would facilitate repair of the diseased or damaged retina. Model systems, like zebrafish, offer an exceptional advantage when studying retinal regeneration, in part because of their robust regenerative powers. The mechanism by which fish successfully regenerate a damaged retina is not known, although we recently provided evidence suggesting Muller glia are involved. The long term goal of our research is to ascertain the role Muller glia play in zebrafish retinal regeneration and identify the mechanisms by which these cells contribute to retinal repair. Ultimately it is hoped that this information can be applied to the mammalian retina to improve its regenerative ability. We propose to use a combination of cell and molecular biological approaches to investigate the role Muller glia play in retinal regeneration. Specifically we propose to: 1) Determine if Muller glia mediate regeneration of all major retinal cell types in the regenerating retina;2) Determine if Muller glia are necessary for successful retina regeneration;3) Identify the genetic changes that impart a progenitor status to Muller glia following retinal injury;and 4) Identify mechanisms underlying a1T gene expression and Muller glia dedifferentiation during retinal regeneration. These studies will form the foundation for future investigations of Muller glia as a source of cells for retinal repair in fish and mammals. Unlike mammals, injury to the fish retina initiates a regenerative response that can restore lost visual function. Our research aims to identify the mechanisms underlying successful retina regeneration in fish. We propose that these mechanisms may suggest new strategies for improving repair of the damaged or diseased mammalian retina.